The long-term goal of our research is to identify the cause(s) of Parkinson's disease. This proposal features an integrative approach to the investigation of (1) cellular mechanisms involved in neurodegeneration, (2) environmental determinants that affect disease risk, and (3) genetic factors that may affect susceptibility. It is composed of four different integrative research projects, and three cores (administrative, research development, and information outreach), which together make up a Coordinated Center for Parkinson's Disease Environment Research. The broad theme underlying this proposal is that Parkinson's disease results from the interaction between environmental toxicants (such as pesticides or metals), protective factors in the environment (such as nicotine, caffeine) and genetic susceptibility factors. Project 1 (entitled "Genes, Environment & PD: Studies in 4 Unique Cohorts") investigates the separate and combined roles of occupational toxicant exposure (pesticides, metals), genetic variants of membrane transporters of these toxicants and putative neuroprotective behaviors (tobacco & caffeine use) in more than 1000 PD cases and over 1500 controls. Shared diagnostic and exposure assessment in 4 cohorts facilitates combined analyses, while the diverse characteristics of each cohort maximize generalizability. The goal of Project 2 (entitled "Neurotoxicants, Oxidative Stress and Alpha-synuclein") is to investigate the role of oxidative stress as a key contributor to the development of alpha-synuclein aggregation, inclusion body formation and ultimately neuronal injury at the experimental level. The effects of metals/pesticides on these pathological processes will also be assessed. Our third project (entitled "Iron, Oxidative Stress, and Pesticides)," will examine (i) the agerelated susceptibility of the mouse nigrostriatal system to combined damage from iron and pesticide exposure, (ii) the effects of oxidative stress in the context of such exposures, and (iii) ways to protect against these effects. Both Projects 2 and 3 will utilize well-established and novel transgenic models to achieve their scientific goals. Our fourth project (entitled," Nicotine and neuroprotection in nonhuman primates") will explore the effects of nicotine as a potential neuroprotective agent against nigrostriatal injury in a primate model of Parkinson's disease. The hypothesis that this action may be achieved through a receptor mediated stimulation of growth factors will also be examined. These integrative research projects should provide important new insights in the environmental, genetic and cellular factors contributing to Parkinson's disease, and could bring us closer to finding the cause of the disease. Success in these endeavors could lead to new strategies for treatment and even disease prevention.